Sulfamoyl substituted phenethylamine derivatives and process of producing them

ABSTRACT

Novel sulfamoyl-substituted phenethylamine derivatives which exhibit α-adrenergic blocking action and are useful as an antihypertensive agent and an agent for the treatment of congestive heart failure.

This is a continuation of Ser. No. 632,258, filed July 18, 1984, nowU.S. Pat. No. 4,558,156, which is a continuation of Ser. No. 403,006,filed July 29, 1982, now abandoned, which is a division of Ser. No.231,421, filed Feb. 4, 1981, now U.S. Pat. No. 4,373,106.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel sulfamoyl-substituted phenethylaminederivatives and the acid addition salts thereof, and more particularly,to novel sulfamoyl-substituted phenethylamine derivatives and the acidaddition salts thereof which exhibit a strong α-adrenergic blockingaction and are useful as an antihypertensive agent and a treating agentfor congestive heart failure. The invention is further concerned withthe process of producing these derivatives and the acid addition saltsthereof.

2. Description of the Prior Art

British Pat. No. 2,006,772 discloses a series of compounds exhibiting α-and β-adrenergic blocking actions and also the patent discloses that thecompound shown by the following formula exhibits strong α- andβ-adrenergic blocking actions ##STR1##

U.S. Pat. No. 3,860,647 discloses a series of compounds shown by thefollowing general formula ##STR2## wherein R represents hydrogen oralkyl having 1-4 carbon atoms; R' represents alkyl having 1-6 carbonatoms, cycloalkyl having 3-6 carbon atoms, XC₆ H₄ (CH₂)₂ C(CH₃), XC₆ H₄(CH₂)₂ C(CH₃)₂, XC₆ H₄ CH₂ CH(CH₃), or XC₆ H₄ CH₂ CH(CH₃)₂ (wherein Xrepresents hydrogen, hydroxyl or methoxy); and Y represents hydrogen orhydroxy. It is also described in the patent specification that thesecompounds exhibit a β-adrenergic blocking action.

British Pat. No. 902,617 discloses a series of compounds shown by thefollowing general formula ##STR3## wherein R₁ is hydroxyl, methyl,methoxy, etc.; R₂ is hydrogen, methyl, etc.; R₃ is phenyl, benzyl orhydroxy-, methyl-, methoxy-, ethoxy-, chloro- or bromo-substitutedphenyl or benzyl radical, etc.; and R₄ is hydrogen, etc. These compoundsexhibit an α-adrenergic blocking action (see, "J. Med. Chem."; 9,812-818 (1966)) and possess an antihypertensive activity.

Also, in "J. Med. Chem."; 9, 812-818 (1966), there is described that thephenoxyethylamine-type compounds shown by the following general formulapossess an α-adrenergic blocking action; ##STR4## wherein R₁ representso-OCH₃, etc., and R₂ represents o- or p-OCH₃, etc.

SUMMARY OF THE INVENTION

An object of this invention is to provide the novelsulfamoyl-substituted phenethylamine derivatives shown by followinggeneral formula and the acid addition salts thereof which possess ahypotensive activity based on an α-adrenergic blocking action and areuseful as an antihypertensive agent, an agent for the treatment ofcongestive heart failure, etc.

Another object of this invention is to provide the process for producingthe above-described pharmaceutically useful compounds.

That is, according to this invention, there are provided thesulfamoyl-substituted phenethylamine derivatives shown by followinggeneral formula I and the acid addition salts thereof ##STR5## whereinR₁ represents, an amino group or a mono- or di-lower alkylamino group;R₂ represents, a hydroxyl group, a lower alkyl group, or a lower alkoxygroup; R₃ represents, hydrogen atom, halogen atom, a lower alkyl group,a lower alkoxy group, a phenylthio group, or a phenylsulfinyl group; R₄,R₅, R₆, R₇, R₈ and R₉ each represents, hydrogen atom or a lower alkylgroup; R₁₀ represents, hydrogen atom, a lower alkyl group, or a loweralkoxy group; and Y represents oxygen atom or a methylene group; said Ybeing, however, an oxygen atom when R₂ is a hydroxyl group.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Now, the term "lower" used in the above-described formula means astraight or branched carbon chain having 1 to 5 carbon atoms. Therefore,for example, a lower alkyl group includes a methyl group, ethyl group,propyl group, butyl group, pentyl group, isobutyl group, etc., and alower alkoxy group includes a methoxy group, ethoxy group, propoxygroup, butoxy group, etc. Also, in the above-described formula, R₁₀which is a substituent of the benzene ring may be disposed at anyposition of which is ortho, meta or para to the side chain. Furthermore,since the compounds of this invention shown by formula I can readilyform the salts thereof and contain asymmetric carbon atom(s), thecompounds of this invention include the salts thereof, the racemiccompounds thereof, a mixture of the racemic compounds, and eachoptically active substance.

The compounds of formula I and the acid addition salts thereof providedby the present invention exhibit an α-adrenergic blocking action andthus they can be utilized for various treatments. For example, they canbe used as useful agents for the treatments of hypertension, congestiveheart failure, angina pectoris, lower urinary tract dysfunction,prostatic hypertrophy, pheochromocytoma and peripheral vasculardisorders.

The compounds of this invention shown by formula I can be produced bythe following processes.

Process 1:

The compounds of formula I are obtained by reacting the compounds shownby general formula II ##STR6## wherein R represents a hydrogen atom or alower alkyl group and R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and Y have thesame significance as in formula I with a halogenating agent and then, ifdesired, (a) reducing the halogenated product obtained by the abovereaction; or (b) reacting the halogenated product with an alkalinematerial and then reacting the product thus obtained with hydrogeniodide, a lower alcohol, or thiophenol, and further, if desired,oxidizing the product obtained by the reaction with thiophenol.

Process 1 is further described in more detail. That is, according to theprocess, the starting materials shown by formula II described above arereacted with a halogenating agent to provide the compounds shown bygeneral formula I₁ ##STR7## wherein X represents, chlorine atom orbromine atom and R, R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and Y have thesame significance as in formula II, and then, if desired, (a) thehalogenated compounds shown by formula I₁ are reduced to form thecompounds shown by formula I₂ ##STR8## wherein R, R₁, R₂, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀ and Y have the same significance as above described; or(b) the halogenated compounds shown by formula I₁ are treated with analkaline material to form the aziridine compounds shown by the followinggeneral formula III ##STR9## wherein R₁, R₂, R₄, R₅, R₇, R₈, R₉, R₁₀ andY have the same significance as above described, then, the aziridinecompounds are reacted with hydrogen iodide, a lower alcohol, orthiophenol to provide the compounds shown by general formula I₃##STR10## wherein R' represents an iodine atom, a lower alkoxy group ora phenylthio group and R₁, R₂, R₄, R₅, R₇, R₈, R₉, R₁₀ and Y have thesame significance as above described and further, when R' of thecompounds shown by formula I₃ is a phenylthio group, if desired, thecompounds of I₃ are oxidized to provide the compounds shown by generalformula I₄ ##STR11## wherein R₁, R₂, R₄, R₅, R₇, R₈, R₉, R₁₀ and Y havethe same significance as above described.

This process is further schematically shown below, wherein the compoundsshown by formulae I₁, I₂, I₃ and I₄ are the desired compounds of thisinvention. ##STR12##

The reaction condition in each step described above is as follows:

Step 1:

The halogenation of the compounds of formula II can be performed in anorganic solvent such as toluene, methyl ethyl ketone, acetonitrile,tetrahydrofuran, etc., at room temperature or under heating using ahalogenating agent such as thionyl chloride, hydrogen chloride, hydrogenbromide, phosphorus trichloride, phosphorus pentachloride, phosphorusoxychloride, thionyl bromide, etc.

Step 2:

The reduction of the compounds of formula I₁ can be performed in anorganic solvent such as methanol, ethanol, toluene, acetonitrile,tetrahydrofuran, etc., under a hydrogen stream, at normal temperatureand normal pressure using a catalyst such as platinum oxide, palladiumcarbon, etc.

Step 3:

The compounds of formula III can be obtained by treating the compoundsof formula I₁ (wherein, however, R and R₆ are hydrogen atom) with analkaline material such as sodium carbonate, metal alcoholate, sodiumhydroxide, potassium hydroxide, etc., in an organic solvent such asethyl acetate, ethanol, dioxane, benzene, etc., at room temperature to50° C.

Step 4:

(i): The compounds of formula I₃ (wherein, R' is a phenylthio group) canbe obtained by reacting the compounds of formula III with thiophenol inan organic solvent such as methanol, chloroform, ethyl acetate, dioxane,benzene, etc., at room temperature.

(ii): The compounds of formula I₃ (wherein, R' is a lower alkoxy group)can be obtained by reacting the compounds of formula III with a loweralcohol in the presence of a BF₃ catalyst under the same condition as inthe step (i).

(iii): The compounds of formula I₃ (wherein, R' is an iodine atom) canbe obtained by reacting the compounds of formula III with hydroiodicacid in an organic solvent such as dioxane, methanol, etc., at roomtemperature.

Step 5:

The oxidation of the compounds of formula I₃ (wherein R' is a phenylthiogroup) can be performed in acetic acid at a temperature of 50°-60° C.using H₂ O₂ as the oxidizing agent.

In addition, among the compounds of this invention, the compounds shownby the following general formula I₅ ##STR13## wherein R" represents alower alkoxy group or a phenylthio group and R, R₁, R₂, R₄, R₅, R₆, R₇,R₈, R₉, R₁₀ and Y have the same significance as above described can beobtained by reacting the compounds of formula I₁ directly with a loweralcohol or thiophenol.

The starting materials of formula II (wherein R is hydrogen atom) usedin the process of this invention are described in British Pat. No.2,006,772 and also the starting materials of formula II (wherein R is alower alkyl group) can be obtained by reacting the compounds of thefollowing formula ##STR14## described in the aforesaid British patentwith a Grignard reagent (lower alkyl-MgX).

Process 2:

Among the compounds of formula I, the compounds of this invention shownby following general formula I₆ ##STR15## wherein R₁, R₂, R₃, R₄, R₇,R₈, R₉, R₁₀ and Y have the same significance as in the formula I, can beproduced by condensing the compound shown by the general formula##STR16## and the compound shown by the following formula ##STR17## andthen reducing the products thus obtained.

This reaction is performed by condensing the compounds of formula IV andthe compounds of formula V in an organic solvent such as methanol,ethanol, toluene, acetonitrile, tetrahydrofuran, etc., and then reducingthe products in the presence of a PtO₂ catalyst or a Raney nickelcatalyst or with NaBH₄, LiAlH₄, etc.

The isolation and purification of the compounds of this invention shownby general formulae I₁ -I₆ formed by Process 1 and 2 are performed byfiltration, extraction with a solvent, separation by columnchromatography, recrystallization, etc.

The pharmacological effects of the compounds of this invention weredetermined by the following experiments. The effects of the typicalcompounds of this invention were compared with5-{1-hydroxy-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide(Compound A) which is one of the typical compounds disclosed in BritishPat. No. 2,006,722 and phentolamine.

A. α-Adrenergic blocking action:

The blood pressure was measured in the rats anesthetized with urethaneand treated with pentolinium. The effects of the test samples(intravenous injection) to antagonize the hypertensive response tophenylephrine (10 μg/Kg i.v.) were measured and the results were shownin Table I.

B. Antihypertensive effects in spontaneously hypertensive rats:

Oral administration: The systolic blood pressure was measured indirectlyfrom the tail cuff method using a programmed electrosphygmanometer(Narco Bio-Systems Inc., PE-300) on spontaneously hypertensive ratshaving a systolic blood pressure higher than 150 mmHg, the result beingshown in Table II.

                  TABLE I                                                         ______________________________________                                        α-Adrenergic blocking action:                                                             α-adrenergic blocking                                 Sample            ED.sub.50 (mg/Kg) i.v.                                      ______________________________________                                        Compounds of this                                                             invention (Ex. No.)                                                            4                0.00035                                                      5                0.00026                                                     10                0.0059                                                      11                0.012                                                       12                0.0073                                                      15                0.0013                                                      16                0.0008                                                      20                0.00000014                                                  25                0.0012                                                      26                0.004                                                       Known compounds                                                               Compound A        0.034                                                       Phentolamine      0.061                                                       ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Antihypertensive effect:                                                                              Change in systolic blood                                                      pressure (mmHg) at stated                             Sample      Dose (mg/Kg)                                                                              dose p.o.                                             ______________________________________                                        Compounds of this                                                             invention (Ex. No.)                                                           10          10          -57 ± 5.6                                          11          30          -50 ± 4.7                                          12          10          -48 ± 2.0                                          15          10          -54 ± 6.2                                          16          10           -71 ± 11.1                                        20           3          -57 ± 4.2                                          25          10          -46 ± 3.6                                          26          10          -46 ± 4.3                                          Known compounds                                                               Compound A  10          -35 ± 6.4                                          Phentolamine                                                                              10          +7.8 ± 5.0                                         Phentolamine                                                                              100          -70 ± 10.1                                        ______________________________________                                    

The clinical administration of the compounds of this invention isusually practiced by intravenous injection or orally as the free basesor the acid addition salts thereof (e.g., hydrochlorides, sulfates,maleates, acetates, furarates, lactates, citrates, etc.). It is properto administer 10 ng-1 mg per ounce of the compound several times per dayin case of intravenous administration or 0.1-100 mg of the compound twoor three times per day in the case of oral administration.

The compounds of this invention may be formulated into ordinary dosageforms such as, for example, tablets, capsules, pills, solutions, etc.,and in these cases, the medicaments can be prepared by conventionalmethods with conventional pharmaceutical excipients.

Then, the production of the compounds of this invention will be furtherdescribed in the following examples. In addition, the starting materialsused in this invention include novel compounds and the productionthereof are shown in the Reference Examples.

REFERENCE EXAMPLE 1 ##STR18##

(1) To 250 g of chlorosulfonic acid was added dropwise 50 g of4-methoxyphenylacetone at 0°-5° C. After stirring the mixture for 4hours at room temperature, the reaction mixture was poured into 2,500 mlof ice water and extracted three with 500 ml of ethyl acetate. Theextract was washed with water and after drying the extract withanhydrous magnesium sulfate, the solvent was distilled off under reducedpressure. The crude crystals obtained were recrystallized frombenzene-ether to provide 32 g of3-chlorosulfonyl-4-methoxyphenylacetone. Melting point: 80°-81° C.

(2) In 26 ml of tetrahydrofuran was dissolved 2.6 g of3-chlorosulfonyl-4-methoxyphenylacetone and then 1.2 g of 40%methylamine was added dropwise to the solution at a temperature lowerthan 10° C. After stirring the mixture for one hour at room temperature,the solvent was distilled off under reduced pressure and the residue wasextracted with ethyl acetate. The extract was washed with water andafter drying with anhydrous magnesium sulfate, the solvent was distilledoff under reduced pressure. The crude crystals obtained wererecrystallized from isopropanol-ether to provide 1.8 g of4-methoxy-3-N-methylsulfamylphenylactone.

Melting point: 100°-101° C.

REFERENCE EXAMPLE 2 ##STR19##

By reacting 2.6 g of 3-chlorosulfonyl-4-methoxyphenylacetone and 0.6 gof dimethylamine in the same manner as in Reference Example 1-(2), 2.5 gof oily 4-methoxy-3-N,N-dimethylsulfamylphenylacetone was obtained.

Nuclear magnetic resonance spectra (CDCl₃): ##STR20##

EXAMPLE 1 ##STR21##

In 1,000 ml of acetonitrile was suspended 17 g of5-{2-[2-(2-ethoxyphenoxy)ethylamino]-1-hydroxy-2-methyl-ethyl}-2-methoxybenzenesulfonamidehydrochloride and while stirring the suspension, 9 g of thionyl chloridewas added dropwise to the suspension at room temperature, whereby theproduct was dissolved and then began to crystallize gradually. Afterstirring the mixture for two days, the crystals formed were recovered byfiltration, washed with chloroform and dried to provide 15 g of5-{1-chloro-2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-methoxybenzenesulfonamidehydrochloride.

The product has the following physicochemical properties.

Melting point: 197°-200° C.

Elemental analysis for C₂₀ H₂₇ N₂ O₅ SCl.HCl:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        Calcd.:  50.11         5.89    5.84                                           Found:   50.06         5.96    5.95                                           ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD):

    ______________________________________                                        Nuclear magnetic resonance spectra (CD.sub.3 OD):                             ______________________________________                                        δ:                                                                              1.30         (3H, d, CH--CH.sub.3)                                            1.40         (3H, t, CH.sub.2 --CH.sub.3)                                     3.63         (2H, t, CH.sub.2 --CH.sub.2 --N)                                 4.01         (3H, s, O--CH.sub.3)                                             4.12         (2H, q, CH.sub.3 --CH.sub.2 --O)                                 4.36         (2H, t, CH.sub.2 --CH.sub.2 --O)                                 5.30         (1H, d, Cl--CH)                                          ______________________________________                                    

The compounds in Examples 2 and 3 were obtained in the same manner as inExample 1.

EXAMPLE 2 ##STR22##

5-{1-Chloro-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamidehydrochloride.

Physiochemical properties:

Melting point: 190°-191° C.

Elemental analysis for C₁₈ H₂₃ N₂ O₄ SCl.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              49.66        5.56    6.43                                          Found:     49.51        5.70    6.53                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO): ##STR23##

EXAMPLE 3 ##STR24##

5-{1-Chloro-2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-methoxybenzenesulfonamidehydrochloride.

Physiochemical properties:

Melting point: 195°-197° C. (decomposed).

Elemental analysis for C₁₉ H₂₅ N₂ O₅ SCl.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              49.04        5.63    6.02                                          Found:     49.02        5.64    6.08                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD+d₆ -DMSO): ##STR25##

EXAMPLE 4 ##STR26##

A mixture of 1.4 g of 4-methoxy-3-N-methylsulfamylphenylacetone, 1 g of2-methoxyphenoxyethylamine, and 30 ml of methanol was refluxed for onehour. After cooling the mixture, 60 mg of a platinum oxide catalyst wasadded thereto, the reduction was performed at normal temperature andpressure. After absorbing a theoretical amount of hydrogen, the catalystwas filtered away. After the filtrate was acidified with an alcoholic 5%hydrochloric acid, the solvent was distilled off under reduced pressureto form 1.6 g of crystals, which were recovered and recrystallized toprovide 1.2 g of the colorless crystals of2-methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-N-methylbenzenesulfonamidehydrochloride.

The product has the following physicochemical properties.

Melting point: 162°-163° C.

Elemental analysis for C₂₀ H₂₈ N₂ O₅ S.HCl:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        Calcd.:  53.99         6.57    6.30                                           Found:   53.85         6.70    6.27                                           ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO):

    ______________________________________                                        δ:                                                                              1.15          (3H, d, --CHCH.sub.3)                                           3.76 and 3.88 (3H + 3H, S, O--CH.sub.3)                               ______________________________________                                    

The product of Example 5 was obtained in the same manner as in Example4.

EXAMPLE 5 ##STR27##

2-Methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-N,N-dimethylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 185°-187° C.

Elemental analysis for C₂₁ H₃₀ N₂ O₅ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              54.95        6.81    6.10                                          Found:     54.73        6.88    5.85                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO):

    ______________________________________                                        δ:                                                                          1.16        (3H, d, CHOH.sub.3), 2.71 (6H, s, N(CH.sub.3).sub.2)              3.76 and 3.87                                                                             (3H + 3H, s, --O--CH.sub.3)                                   ______________________________________                                    

REFERENCE EXAMPLE 3 ##STR28##

In 50 ml of ethyl acetate was suspended 4.35 g (0.01 mole) of5-{1-chloro-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamidehydrochloride and then 50 ml of an aqueous 10% sodium carbonate solutionwas added to the suspension with stirring. After further stirringovernight vigorously, the reaction mixture was recovered by decantation.After removing inorganic materials by passing the ethyl acetate layerthus recovered through a silica gel column (50 ml of silica gel), thereaction product was evaporated to dryness to provide 3.2 g (88%) ofcolorless resinous5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide.

The product has the following physicochemical properties.

Amorphous form.

Elemental analysis for C₁₈ H₂₂ N₂ O₄ S:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        Calcd.:  59.65         6.12    7.73                                           Found:   59.37         6.12    7.61                                           ______________________________________                                    

Nuclear magnetic resonance spectra (CDCl₃): ##STR29##

EXAMPLE 6 ##STR30##

In 50 ml of dioxane was dissolved 2.5 g of5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamideand after adding thereto 1 g of concentrated hydroiodic acid, themixture was stirred overnight. After the reaction was over, the solventwas distilled off under reduced pressure and the residue was washedthree with 30 ml of water and then three with 200 ml of ether andcrystallized by the addition of ethyl acetate. The crystals wererecovered by filtration, washed with water, and dried to provide 1.7 gof5-{1-iodo-2-[2-(2-methoxyphenoxyethylamino]ethyl}-2-methylbenzenesulfonamidehydroiodide.

The product has the following physicochemical properties.

Melting point: 154°-155° C.

Elemental analysis for C₁₈ H₂₃ N₂ O₄ SI.HI:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        Calcd.:  34.97         3.91    4.53                                           Found:   35.07         3.98    4.39                                           ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR31##

EXAMPLE 7 ##STR32##

In 50 ml of methanol was dissolved 2.5 g of5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamideand after adding 1 g of thiophenol to the solution and stirringovernight the mixture at room temperature, methanol was distilled off.The residue was applied to a silica gel column chromatography and theproduct was eluted with a mixed solvent of chloroform and methanol (9:1by volume ratio) to provide 2.4 g of5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamideas a viscous oily material.

The product has the following physicochemical properties.

Amorphous form.

Elemental analysis for C₂₄ H₂₈ N₂ O₄ S₂ :

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        Calcd.:  60.99         5.97    5.93                                           Found:   60.72         6.11    5.71                                           ______________________________________                                    

Nuclear magnetic resonance spectra (CDCl₃): ##STR33##

EXAMPLE 8 ##STR34##

In 50 ml of methanol was dissolved 2.5 g of5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamideand after adding thereto 2 ml of a boron trifluoride ether complex atroom temperature, the mixture was stirred overnight. Thereafter,methanol was distilled off under reduced pressure and the residue wasapplied to a silica gel column chromatography. The product was theneluted with a mixed solvent of chloroform and methanol (9:1 by volumeratio), whereby 1.5 g of a colorless viscous oily material was obtained.The product was crystallized by the addition of 5 ml of methanol andseveral drops of ammonia. The crystals formed were recovered byfiltration, washed with water, and dried to provide 1.2 g of5-{1-methoxy-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide.

The product has the following physicochemical properties.

Melting point: 150°-152° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₅ S:

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        Calcd.:  57.85         6.64    7.10                                           Found    57.58         6.79    7.24                                           ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR35##

EXAMPLE 9 ##STR36##

In 20 ml of acetic acid was dissolved 2 g of5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamideand after adding thereto 0.5 ml of 30% H₂ O₂, the mixture was heated to50°-60° C. for 3 hours. After adding thereto 100 ml of water, thereaction mixture was extracted with 200 ml of ethyl acetate. The ethylacetate extract was washed with an aqueous 1% sodium carbonate solutionand then ethyl acetate was distilled off under reduced pressure. Theresidue was applied to a silica gel column chromatography, the productwas eluted with a mixed solvent of chloroform and methanol (9:1 byvolume ratio), and the colorless viscous oily product thus obtained wascrystallized by the addition of ethyl acetate. The crystals formed wererecovered by filtration to provide 1.3 g of5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylsulfinylethyl}-2-methylbenzenesulfonamide.

The product has the following physicochemical properties.

Melting point: 139°-141° C.

Elemental analysis for C₂₄ H₂₈ N₂ O₅ S₂ :

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        Calcd.:  59.00         5.78    5.73                                           Found:   58.91         5.74    5.72                                           ______________________________________                                    

EXAMPLE 10 ##STR37##

In 150 ml of methanol was dissolved 3.8 g of5-{1-chloro-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methoxybenzenesulfonamidehydrochloride and after adding thereto 0.5 g of 10% palladium carbon, itwas dechlorinated under a hydrogen stream at normal temperature andpressure. Then, palladium carbon was filtered away and the filtrate wasconcentrated under reduced pressure to provide 3.1 g of2-methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]ethyl}benzenesulfonamidehydrochloride, which was recrystallized from 120 ml of a mixture ofmethanol and ethanol (1:4 by volume ratio) to provide 2.3 g of thecolorless crystals thereof.

The product has the following physicochemical properties.

Melting point: 196°-198° C.

Elemental analysis for C₁₈ H₂₄ N₂ O₅ S.HCl):

    ______________________________________                                               C (%)       H (%)   N (%)                                              ______________________________________                                        Calcd.:  51.86         6.04    6.72                                           Found:   51.72         6.23    6.68                                           ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD):

    ______________________________________                                        δ:                                                                              3.84 and 3.98 (3H + 3H, s, --OCH.sub.3)                                       4.24          (2H, t, --OCH.sub.2 --)                                 ______________________________________                                    

The compounds in Examples 11-29 were obtained in the same manner as inExample 10.

EXAMPLE 11 ##STR38##

5-{2-[2-(2-Methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 173°-175° C.

Elemental analysis for C₁₈ H₂₄ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              53.93        6.28    6.99                                          Found:     53.83        6.27    6.97                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR39##

EXAMPLE 12 ##STR40##

5-{2-[2-(2-Ethoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 180°-181.5° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              55.00        6.56    6.75                                          Found:     54.81        6.56    6.89                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR41##

EXAMPLE 13 ##STR42##

5-{2-[2-(2-Methoxyphenoxy)-1-methylethylamino]ethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 169°-171° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              55.00        6.56    6.75                                          Found:     54.89        6.60    6.76                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR43##

EXAMPLE 14 ##STR44##

5-{2-[3-(2-Methoxyphenyl)-1-methylpropylamino]ethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 198°-200° C.

Elemental analysis for C₂₀ H₂₈ N₂ O₃ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              58.17        7.08    6.78                                          Found:     58.09        7.01    6.62                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO): ##STR45##

EXAMPLE 15 ##STR46##

2-Hydroxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]ethyl}benzenesulfonamide.

Physicochemical properties:

Melting point: 97°-99° C.

Elemental analysis for C₁₇ H₂₂ N₂ O₅ S.H₂ O:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              53.10        6.29    7.29                                          Found:     52.75        6.22    7.09                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO): ##STR47##

EXAMPLE 16 ##STR48##

2-Methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}benzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: above 250° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₅ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              52.96        6.31    6.50                                          Found:     52.44        6.31    6.47                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO): ##STR49##

EXAMPLE 17 ##STR50##

2-Methyl-5-{2-[2-(2-methoxyphenoxy)-1-methylethylamino]ethyl}benzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 183°-185° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₃ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              57.20        6.82    7.02                                          Found:     57.13        6.79    6.99                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR51##

EXAMPLE 18 ##STR52##

2-Methyl-5-[2-(2-phenoxyethylamino)ethyl]benzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 208.5°-210° C.

Elemental analysis for C₁₇ H₂₂ N₂ O₃ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              55.05        6.25    7.55                                          Found:     54.83        6.23    7.48                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR53##

EXAMPLE 19 ##STR54##

5-{2-[2-(2-Methoxyphenoxy)ethylamino]-2,2-dimethylethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 199°-202° C.

Elemental analysis for C₂₀ H₂₈ N₂ O₄ S.HCl.CH₃ OH:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              54.71        7.21    6.08                                          Found:     54.50        7.17    6.14                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO): ##STR55##

EXAMPLE 20 ##STR56##

5-{2-[2-(2-Ethoxyphenoxy)ethylamino]-2-methylethyl}-2-methoxybenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 254°-256° C.

Elemental analysis for C₂₀ H₂₈ N₂ O₅ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              53.99        6.57    6.30                                          Found:     53.79        6.58    6.26                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR57##

EXAMPLE 21 ##STR58##

5-{2-[2-(2-Methoxyphenoxy)ethylamino]-1-methylethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 183°-185° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              55.00        6.56    6.75                                          Found:     54.76        6.56    6.74                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR59##

EXAMPLE 22 ##STR60##

5-{2-[2-(2-Methoxyphenoxy)-2-methylethylamino]ethyl}-2-methylbezenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 231°-232° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              55.00        6.56    6.75                                          Found:     54.86        6.58    6.83                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR61##

EXAMPLE 23 ##STR62##

5-{2-[2-(2-Methoxyphenoxy)-1,1-dimethylethylamino]ethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 191°-193° C.

Elemental analysis for C₂₀ H₂₈ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              56.00        6.81    6.53                                          Found:     55.83        6.86    6.32                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO): ##STR63##

EXAMPLE 24 ##STR64##

5-{2-[N-[2-(2-Methoxyphenoxy)ethyl]-N-methylamino]ethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 169°-171° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              55.00        6.56    6.75                                          Found:     54.88        6.51    6.64                                          ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSD): ##STR65##

EXAMPLE 25 ##STR66##

5-{2-[2-(2-Methoxyphenoxy)ethylamino]-2-methylethyl}-2-methylbenzenesulfonaimdehydrochloride.

Physicochemical properties:

Melting point: 250°-252° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              55.00        6.56    6.75                                          Found:     54.68        6.49    6.58                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CDCl₃ +d₆ -DMSO+D₂ O+Na₂ CO₃)##STR67##

EXAMPLE 26 ##STR68##

5-{2-[2-(2-Methoxyphenoxy)ethylamino]-2-ethylethyl}-2-methylbenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 198°-200° C.

Elemental analysis for C₂₀ H₂₈ N₂ O₄ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              56.00        6.81    6.53                                          Found:     55.76        6.88    6.51                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CDCl₃ +d₆ -DMSO+D₂ O+Na₂ CO₃):##STR69##

EXAMPLE 27 ##STR70##

2-Hydroxy-5-{2-[2-(4-methoxyphenoxy)ethylamino]ethyl}benzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 237°-241° C. (decomposed).

Elemental analysis for C₁₇ H₂₂ N₂ O₅ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              50.68        5.75    6.95                                          Found:     50.45        5.64    6.99                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD):

    ______________________________________                                        γ: 3.74 (3H, s, O--CH.sub.3), 4.22 (2H, t, --CH.sub.2 --O)              ______________________________________                                    

EXAMPLE 28 ##STR71##

2-Hydroxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}benzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 211°-214° C.

Elemental analysis for C₁₈ H₂₄ N₂ O₅ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              51.86        6.04    6.72                                          Found:     51.72        6.00    6.59                                          ______________________________________                                    

Nuclear magnetic resonance (CD₃ OD): ##STR72##

EXAMPLE 29 ##STR73##

5-{2-[2-(2-Ethoxyphenoxy)ethylamino]-2-methylethyl}-2-hydroxybenzenesulfonamidehydrochloride.

Physicochemical properties:

Melting point: 172°-173° C.

Elemental analysis for C₁₉ H₂₆ N₂ O₅ S.HCl:

    ______________________________________                                                 C (%)      H (%)   N (%)                                             ______________________________________                                        Calculated:                                                                              52.96        6.31    6.50                                          Found:     52.83        6.65    6.12                                          ______________________________________                                    

Nuclear magnetic resonance spectra (CD₃ OD): ##STR74##

The starting materials and the reaction types applied to prepare theproducts of the above Examples 2, 3, 5 and 11-29 are shown belowschematically;

    ______________________________________                                        Exam-                                                                         ple No.                                                                             Starting Material & Reaction Type                                       ______________________________________                                               ##STR75##                                                              3                                                                                    ##STR76##                                                              5                                                                                    ##STR77##                                                              11-29                                                                                ##STR78##                                                              ______________________________________                                         (X represents halogen; R, R.sub.1, R.sub.2 and R.sub.4 -R.sub.10 in the       formula represent the same group as the corresponding group of the aimed      compound)                                                                

What is claimed is:
 1. Sulfamoyl-substituted phenethylamine derivativesrepresented by the general formula ##STR79## wherein R₁ represents anamino group or a mono- or di-lower alkylamino group; R₂ represents ahydroxyl group, a lower alkyl group, or a lower alkoxy group; R₃represents a hydrogen atom, a lower alkoxy group or a lower alkyl group;R₄, R₅, R₆, R₇, R₈, and R₉ each represents a hydrogen atom or a loweralkyl group; R₁₀ represents a hydrogen atom, a lower alkyl group, or alower alkoxy group; and Y represents an oxygen atom, and the saltsthereof.
 2. A pharmaceutical composition containing an effectiveα-adrenergic antagonistic amount of a compound of claim 1 and apharmaceutically acceptable excipient.
 3. The salts of thesulfamoyl-substituted phenethylamine derivatives as claimed in claim 1wherein R₃ is a lower alkyl group or a lower alkoxy group.
 4. Thecompound of claim 1 wherein R₃ is a hydrogen atom and the salts thereof.5. The compound of claim 1 wherein R₃ is a lower alkyl group and thesalts thereof.
 6. The compound of claim 1 which is a racemic compound.7. The compound of claim 1 which is a mixture of racemic compounds. 8.The compound of claim 1 which is an optically active isomer.
 9. Theisomer of claim 8 which is the (+) isomer.
 10. The isomer of claim 8which is the (-) isomer.
 11. The optically active isomers of thecompound of claim
 7. 12. The isomer of claim 11 which is the (+) isomer.13. The isomer of claim 11 which is the (-) isomer.
 14. The compound ofclaim 1 which is5-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-methoxybenzenesulfonamide.15. The compound of claim 1 which is2-methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}benzenesulfonamide.16. The compound of claim 1 which is5-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-methylbenzenesulfonamide.17. The compound of claim 1 which is5-{2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide.18. The compound of claim 1 which is2-methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-N-methylbenzenesulfonamide.19. The compound of claim 1 which is2-methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-N,N-dimethylbenzenesulfonamide.